Identification and mechanism of G protein-biased ligands for chemokine receptor CCR1.

ABSTRACT: Biased signaling of G protein-coupled receptors describes an ability of different ligands that preferentially activate an alternative downstream signaling pathway. In this work, we identified and characterized different N-terminal truncations of endogenous chemokine CCL15 as balanced or biased agonists targeting CCR1, and presented three cryogenic-electron microscopy structures of the CCR1-G_i complex in the ligand-free form or bound to different CCL15 truncations with a resolution of 2.6-2.9 Å, illustrating the structural basis of natural biased signaling that initiates an inflammation response. Complemented with pharmacological and computational studies, these structures revealed it was the conformational change of Tyr291 (Y291^7.43) in CCR1 that triggered its polar n

SUBMITTER: Shao Z 

PROVIDER: S-EPMC8885419 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature